Alzheimer's disease is a nervous disease which exhibits a decline in cognitive function (for example, memory disorder) as a main symptom. Although Alzheimer's disease frequently develops in the elderly, there is not effective therapeutic drug, and this has become a big problem in developed countries in which the society is aging. In postmortem brains of patients with Alzheimer's disease, senile plaques are found. These are known to be aggregates of “amyloid β protein”. The fact that amyloid βprotein is the main cause of Alzheimer's disease is widely accepted based on a number of studies.
Amyloid β protein is produced from its precursor, “amyloid precursor protein”. Amyloid precursor protein is a membrane protein present on the nerve cell membrane. In normal brain, cleavage of the extracellular domain of amyloid precursor protein with α-secretase followed by cleavage of the domain inside the cell membrane with γ-secretase causes production and extracellular release of a peptide called p3. This is called “non-amyloidgenic pathway”, and amyloid β protein is not produced in the pathway (Non-patent Document 1). In normal brain, only several percent of the extracellular domain undergoes cleavage by β-secretase, to cause extracellular secretion of amyloid β protein. On the other hand, it has been thought that the brain of a patient developing Alzheimer's disease exhibits increased production of amyloid β protein, or production of a molecular species of amyloid β protein having higher aggregability. Due to the property of amyloid β protein to cause aggregation, senile plaques (amyloid aggregates) are finally formed in patients with Alzheimer's disease, and these senile plaques are found as deposition in the brain.
After being cleaved out, amyloid β protein gradually aggregates to finally form senile plaques (amyloid aggregates). The “oligomer (which is composed of several amyloid β protein units associated with each other)” produced during the aggregation process is known to have strong neurotoxicity. From both in vitro and in vivo studies, the oligomer of amyloid β protein is reported to inhibit synaptic plasticity, which is a neurological phenomenon indispensable for memory and learning (Non-patent Documents 2 and 3) it is also reported that administration of the oligomer into the brain of a mouse causes loss of memory and learning ability (Non-patent Documents 4 and 5). A recent study also reported that long-term exposure to the oligomer causes neuronal death and the like (Non-patent Document 6). The oligomer is therefore attracting attention as a causative substance for development of Alzheimer's disease.
Thus, in spite of the fact that amyloid β protein is widely recognized as a cause of Alzheimer's disease, the therapeutic drugs for Alzheimer's disease that are clinically used at present are not designed such that they act on amyloid β protein. More specifically, donepezil (Patent Document 1) and memantine (Patent Document 2), which are used as therapeutic drugs for Alzheimer's disease, act as an acetylcholine esterase inhibitor and an NMDA receptor inhibitor, respectively, and do not interact with amyloid β protein. Since these are the so called symptomatic drugs, they have no drastic action to ameliorate Alzheimer's disease at present.
Under such circumstances, development of novel therapeutic drugs for Alzheimer's disease based on the action mechanism (associated with amyloid protein) is in progress. In an attempt to suppress production of amyloid β protein from amyloid precursor protein, secretase regulating agents are being developed (Non-patent Document 1). In particular, development of γ-secretase inhibitors is most rapidly progressing, and Semagacestat (Patent Document 3), Begacestat (Patent Document 4), and the like have been clinically developed one after another. Another therapeutic method which is drawing attention is an antibody therapy based on recognition and elimination of amyloid β protein in the brain by an antibody. Bapineuzumab (Patent Document 5), solanezumab, and the like have been actually clinically developed so far.
However, the therapeutic drugs for Alzheimer's disease having action mechanisms associated with amyloid protein which are mainly developed at present are known to have problems. In terms of γ-secretase inhibitors, it is known that the substrate for γ-secretase is originally not limited to amyloid precursor protein, and that there are about 100 kinds of its substrates (Non-patent Document 7). Since the Notch receptor, which is important for cell differentiation, is included in such substrates (Non-patent Document 8), there is a concern that side effects may occur. Actually, development of Semagacestat, which had been a major candidate for a γ-secretase inhibitor, was stopped after the phase III clinical trial in 2010. The antibody therapy using an anti-amyloid β antibody may cause angiitis, vasogenic cerebral edema, and/or the like. Actually, development of Bapineuzumab, which had been a promising agent for antibody therapy, was stopped in 2012.
Some γ-secretase substrates are known to release their extracellular domains after cleavage, similarly to the amyloid peptide (Non-patent Documents 9 and 10). Since these peptides can be used as indices of γ-secretase, there are several inventions that attempt to use the cleaved fragments as biomarkers for Alzheimer's disease (Patent Documents 6 and 7). It is also known that the membrane protein called Alcadein -β in the living body is cleaved both by γ-secretase and by α-secretase, resulting in production of a peptide composed of 37 amino acids (VLSSQQFLHRGHQPPPEMAGHSLASSHRNSMIPSAAT) (Non-patent Document 11).
However, an idea to use such a peptide as a regulating agent for Alzheimer's disease is difficult to expect under the current levels of knowledge and technology, and, accordingly, there has been no report on such an idea.